Ovarian cancer is the leading cause of death from gynecologic cancer. Despite high initial tumor response rates of 80% to surgical debulking and chemotherapy, most women with advanced ovarian cancer will eventually develop drug-resistant disease. Because second-line chemotherapeutic agents provide a response rate of only 15-25%, there is clearly a need to develop better therapeutic strategies. Small interfering RNAs (siRNAs) are a class of RNA molecules that previously have been demonstrated to be highly effective in inactivating cancer-causing genes (oncogenes) in cancer cells grown in culture. However, the development of siRNAs as clinically significant therapeutic agents has been hampered by the fact that siRNAs are extremely unstable at physiological conditions. In addition, there has been no effective way to target these potentially therapeutic molecules specifically to cancer cells. We have recently demonstrated that gelatinous-like nanoparticles called nanogels can be easily loaded with siRNAs and targeted to deliver their potentially therapeutic payload to ovarian cancer cells grown in culture. Nanogels protect the siRNA molecules from degradation until released into the cancer cells. The proposed studies seek to demonstrate that these non-toxic nanogels can be used to effectively target siRNAs to cancer cells in living organisms (experimental mice) as well. Such studies are pre-requisite to the potential clinical application of the technology for the treatment of cancer in humans. Specifically, siRNAs directed against the EGFR (epidermal growth factor receptor) gene will be loaded into nanogels engineered to specifically target proteins expressed on the surface of ovarian cancer cells. The EGFR gene is highly expressed in ovarian and most other types of cancer cells and is known to induce cells to rapidly divide and become resistant to most commonly used chemotherapy agents. Thus, the inactivation of EGFR in cancer cells has great therapeutic value. Demonstration that nanogels can be an effective vehicle for the delivery of therapeutic siRNAs to cancer cells in mice will open the door to the development of this exciting new technology of clinical application in humans. PUBLIC HEALTH RELEVANCE: The ability to deliver siRNA against oncogenes specifically targeted to cancer cells will be a major contribution to the treatment of cancer. Development of a mouse model in which to demonstrate and refine this targeted delivery nanotechnology is a key step in moving the technology into clinical practice.